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Glycogen Synthase Kinase-3ß Participates in Nuclear Factor B–Mediated Gene Transcription and Cell Survival in Pancreatic Cancer Cells

¹ Division of Oncology Research and ² GI Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota

Requests for reprints: Daniel D. Billadeau, Mayo Clinic, Division of Oncology Research, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-266-4334; Fax: 507-266-5146; E-mail: billadeau.daniel{at}mayo.edu.

Recent studies using glycogen synthase kinase-3ß (GSK-3ß)–deficient mouse embryonic fibroblasts suggest that GSK-3ß positively regulates nuclear factor B (NFB)–mediated gene transcription. Because NFB is suggested to participate in cell proliferation and survival pathways in pancreatic cancer, we investigated the role of GSK-3ß in regulating these cellular processes. Herein, we show that pancreatic cancer cells contain a pool of active GSK-3ß and that pharmacologic inhibition of GSK-3 kinase activity using small molecule inhibitors or genetic depletion of GSK-3ß by RNA interference leads to decreased cancer cell proliferation and survival. Mechanistically, we show that GSK-3ß influences NFB-mediated gene transcription at a point distal to the I kinase complex, as only ectopic expression of the NFB subunits p65/p50, but not an I kinase ß constitutively active mutant, could rescue the decreased cellular proliferation and survival associated with GSK-3ß inhibition. Taken together, our results simultaneously identify a previously unrecognized role for GSK-3ß in cancer cell survival and proliferation and suggest GSK-3ß as a potential therapeutic target in the treatment of pancreatic cancer.

Key Words: GSK-3 • NF-B

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